Antibiotic Sensitivity Patterns in Children with Urinary Tract Infection: Retrospective Study Over 8 Years in a Single Center

DOI: https://doi.org/10.3339/jkspn.2019.23.1.22 ISSN 2384-0250 (online)

Antibiotic Sensitivity Patterns in Children with Urinary Tract Infection: Retrospective Study Over 8 Years in a Single Center

Purpose: We studied the pathogens and trends in antibiotic sensitivity pattern in children with urinary tract infection (UTI) over 8 years in order to evaluate adequate treatment.

Methods: We performed a retrospective review of medical records of children with UTI from January 2009 to December 2016 in Daegu Fatima Hospital. Uropa- thogens and antibiotic sensitivity patterns were selected. Only 1 bacterial species with a colony count of ≥105 CFU/mL was considered a positive result. We com- pared 2 periods group (A: 2009~2012, B: 2013~2016) to investigate trends of anti- biotic sensitivity pattern.

Results: During the 8 year period, 589 cases are identified (E. coli was cultured in 509 cases, 86.4%). Among all patients, this study investigated the antibiotic sen- sitivity of E. coli. Antimicrobial susceptibility to ampicillin was steadily low for both periods (A: 32.6%, B: 40.1%, P=0.125), and to amikacin was consistently high for both periods (A: 99.4%, B: 99.3%, P=1.000). Antibiotic sensitivity to third-genera- tion cephalosporin decreased from period A to B (A: 91.7%, B: 75.5%, P=0.000).

Antibiotic sensitivity to quinolone significantly decreased from A to B (A: 88.4%, B:

78.2%, P=0.003). The prevalence of extended-spectrum β-lactamase-producing E. coli increased from period A to B (A: 6.1%, B: 17.1%, P=0.000).

Conclusion: This study showed that conventional antibiotic therapy for the treatment of pediatric UTI needs to be reevaluated. A careful choice of antibiotic is required due to the change in antibiotic sensitivity and the emergence of antibiotic-resistant bacteria.

Key words: Urinary tract infection, antibiotic sensitivity, Extended-spectrum β-l actamase

Byungwoo Woo, M.D.

Youngkwon Jung, M.D.

Hae Sook Kim, M.D.

Department of Pediatrics, Daegu Fatima Hospital, Daegu, Korea

Corresponding author: Hae Sook Kim, M.D.

Department of Pediatrics, Daegu Fatima Hospital, 99, Ayang-ro, Dong-gu, 41199, Daegu, , Korea

Tel: +82-53-940-7243 Fax: +82-53-940-7076 E-mail: [email protected] Received: 23 February 2018 Revised: 27 March 2018 Accepted: 19 June 2018

This is an open-access article distributed under the terms of the Creative Commons Attribu tion Non-Commercial License (http://

crea tivecom mons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Copyright © 2019 The Korean Society of Pediatric Nephrology

Introduction

Urinary tract infection (UTI) is one of the most common forms of pediatric bacterial infections and is the second most common infectious disease in children following respiratory infections

. UTI in children manifests as non­

specific symptoms such as fever with uncertain infectious site, which is the

main reason for antibiotic treatment upon visiting the emergency room or

hospitalization

. The prognosis of UTI is good, but long­term complications

can lead to renal insufficiency, hypertension, and chronic kidney failure if

patients have anatomical abnormalities or proper treatment is not initiated

.

For this reason, children with suspected UTI should be started on empirical antibiotic therapy before urine culture results are confirmed, to prevent renal impairment. Accor­

ding to sex and age, the incidence and clinical symptoms vary, and the causative organisms are different in pediatric UTI. In addition, as antibiotic­resistant pathogens change and are increased due to the abuse of antibiotics and inap­

propriate selection, it is necessary to select proper antibiotics in the early phase of treatment. Thus, regular antibiotic sensitivity results from the evaluation of UTI are impor­

tant to improve the effectiveness of treatment.

We performed this study to help in the selection of ap­

propriate antibiotics by investigating the trend of causative bacteria, antibiotic susceptibility and the frequency of ex­

tended­spectrum β­lactamase (ESBL)­producing bacteria in 589 patients with UTI who were admitted to Daegu Fatima Hospital within a period of 8 years.

Materials and methods

1. Patient selection

We retrospectively reviewed the cases of children aged 0 to 12 years who were hospitalized for febrile UTI at the Department of Pediatrics, Daegu Fatima Hospital, from January 2009 to December 2016. We defined febrile UTI as a case of fever with a tympanic temperature of 38℃or more, 5 or more white blood cells per high power field on urine sediment microscopy, and more than 10

colony for­

ming units (CFU)/mL on urine culture analysis. Only 1 bacterial species identified with a colony count of ≥10

CFU/mL was considered a positive result (when two or more strains were cultured, they were excluded). Among toilet­trained children, midstream urine was collected, whereas among children who are not toilet trained, urine was collected by an adhesive sterile collection bag after sterilization of the skin of the genitals.

The distribution of sex and age, distribution of major pathogens, antibiotic sensitivity and antibiotic sensitivity of ESBL­producing E. coli were retrospectively analyzed in 589 patients with UTI.

2. Organism identification and drug susceptibility test

The identification of cultured strains and antibiotic sus­

ceptibility tests were performed based on the Clinical and Laboratory Standards Institute guidelines. Cultures were performed using 5% sheep blood agar plate and MacConkey agar plate, which were inoculated with 0.001 mL of urine each, and incubated at 36℃ in 5% CO

for 48 hours. The formed colonies after culturing were identified by bioche­

mical analysis and those containing more than 10

/mL cultures were judged to be causative organisms of UTI. The strains isolated from urine culture samples were tested for susceptibility to antibiotics used in clinical trials. In our study, we used Microscan

(Dade Behring, Milton Keynes, UK), which is an automated instrument, to assess bacterial identification and antibiotic susceptibility.

3. Statistical analysis

Statistical analysis was performed using SPSS version 18.0 (IBM Corp., Armonk, NY, USA). Chi­square test or Fisher’s exact test (less than 5 values) was used for the an­

alysis of categorical variables, and Chi­square test for trend was used to evaluate the changes according to periods. The mean values of some variables were compared between the two groups using the student’s t­test. A P value less than 0.05 was considered statistically significant.

Results

1. Patient characteristics

Among 589 patients diagnosed with UTI, 382 patients (64.8%) were male, and 207 patients (35.2%) were female;

the male to female ratio was 1.8:1. The mean age of females

was slightly higher than that of males: 5.6 months for males

and 14.3 months for females. In the group younger than 1

year, the male to female ratio was 2.3:1, which showed a

higher number of males (362 cases were males, and 157

cases were females). In the group aged 1 to 2 years, the male

to female ratio was 1:5.4, which showed a higher number

of females (5 cases were males, and 27 cases were females)

(Table 1).

2. Trend of periodic antibiotic sensitivity

We compared 2 periods groups (A: 2009–2012, B: 2013–

2016) to investigate trends of antibiotic sensitivity patterns.

During the 8 year period, 589 cases are collected (E. coli was cultured in 509 cases, 86.4%). Among all patients, this study investigated the antibiotic sensitivity of E. coli. The antimicrobial susceptibility to ampicillin was steadily low (A: 32.6%, B: 40.1%, P=0.125), to amikacin was consistently high (A: 99.4%, B: 99.3%, P=1.000), to trimethoprim/sul­

famethoxazole was steadily moderate (A: 72.1%, B: 70.7%, P=0.757), to carbapenem was steadily high (A: 99.7%, B:

100%, P=1.000), and to piperacillin/tazobactam was stea­

dily high for 2 periods (A: 94.2%, B: 95.9%, P=0.460). These changes were not statistically significant.

Antibiotic sensitivity to third­generation cephalosporin significantly decreased from period A to B (A: 91.7%, B:

75.5%, P=0.000). Antibiotic sensitivity to quinolone sig­

nificantly decreased from A to B (A: 88.4%, B: 78.2%, P=

0.003). Antibiotic sensitivity to monobactam significantly decreased from period A to B (A: 91.4%, B: 77.6%, P=0.000).

The prevalence of ESBL­producing E. coli significantly increased from period A to B (A: 6.1%, B: 17.1%, P=0.000) (Table 2) (Fig. 1).

3. Comparison of two groups with or without sus- ceptibility to third-generation cephalosporin antibiotics

When we compared patients showing susceptibility to third­generation cephalosporins with patients showing resistance, the rate of previous hospitalization was signifi­

cantly lower among the patients who showed susceptibility (10.6% vs. 22.7%, P=0.011). The rate of change of antibiotics after initial treatment failure was also significantly lower in the susceptible group compared to the resistant group (9.5% vs. 21.2%, P=0.011). There were no significant diffe­

rences between the two groups regarding fever duration or age (Table 3).

4. Comparison between the ESBL-producing E. coli infection group and the non-ESBL-producing E.

coli infection group

The ESBL­producing E. coli infection group had a signi­

ficantly higher rate of previous hospitalization compared to the non­ESBL­producing E. coli infection group (24.4%

vs. 10.6%, P=0.005). The rate of change of antibiotics after initial treatment failure was also significantly higher in the Table 1. Age and Sex Distribution of Patients of All Pathogens

and Escherichia coli

Age (yrs) Total, N (%) E.coli, N (%)

Male Female Total Male Female Total

0–1 362 (61.5) 157 (26.6) 519 (88.1) 324 (63.7) 131(25.7) 455 (89.4) 1–2 5 (0.8) 27 (4.6) 32 (5.4) 4 (0.8) 19 (3.7) 23 (4.5)

>2 15 (2.5) 23 (4.0) 386 (6.5) 8 (1.6) 23 (4.5) 31 (6.1) Total 382 (64.8) 207 (35.2) 589 (100) 336 (66.1) 173 (33.9) 509 (100) Table 2. Comparison of Susceptibility of Escherichia coli to Anti- biotics between 2 Periods

Antibiotics

No. (%) of susceptible E. coli

P value 2009–2012 (period A)

(N=362) 2013–2016 (period B) (N=147)

AMP 118 (32.59) 59 (40.13) 0.125

AMK 360 (99.44) 146 (99.31) 1.000

TMP/SMX 261 (72.09) 104 (70.74) 0.757

CBP 361 (99.72) 147 (100) 1.000

TZP 341 (94.19) 141 (95.91) 0.460

3rd CEP 332 (91.70) 111 (75.51) 0.000

QNL 320 (88.39) 115 (78.23) 0.003

MNB 361 (91.43) 114 (77.55) 0.000

ESBL 22 (6.07) 25 (17.06) 0.000

Abbreviations: AMP, ampicillin; AMK, amikacin; TMP/SMX, trimethoprim/

sulfamethoxazole; CBP, carbapenem; TZP, piperacillin/tazobactam; 3

CEP, third-generation cephalosporins; QNL, quinolone; MNB, monobactam;

ESBL, extended-Spectrum β -lactamase.

Fig. 1. Trend in antibiotic susceptibility of Escherichia. coli over 8 years. AMP, ampicillin; AMK, amikacin; TMP/SMX, trimethoprim/

sulfamethoxazole; CBP, carbapenem; TZP, piperacillin/tazobactam;

3

CEP, third-generation cephalosporins; QNL, quinolone; MNB,

monobactam; ESBL, extended-spectrum β-lactamase.

ESBL­producing E. coli group compared to the non­ESBL­

producing E. coli group (22.2% vs. 9.7%, P=0.005). There were no significant differences between the two groups regarding age, sex, fever duration, or blood tests (Table 4).

Discussion

The prevalence of pediatric UTI was 1% in males and 1–3

% in females. Generally, males are diagnosed within the first year of life, while females are diagnosed at 3 years old.

The male to female ratio of pediatric UTI patients varied according to age, from 2.8–5.4:1 within the first year of life and 1:10 between 1 and 2 years of age

. In our study, the age at first diagnosis of UTI was higher in females than males, and the proportion of sex by age also showed a similar ten­

dency. Because the proportion of children younger than 1 year who had a high prevalence rate in males was high, the

overall ratio of male and female patients with UTI showed opposite results in this study.

It is known that 80–90% of pediatric UTIs are caused by E. coli, and 10–15% are caused by Klebsiella, Enterobacter, Proteus, and Pseudomonas

. Enterococci, Pseudomonas, S. aureus, S. epidermidis, Haemophilus influenzae, Group B streptococci can be cultured in children who have uri­

nary tract abnormalities or dysfunction and Lactobacillus species, Corynebacterium species, Coagulase­negative staphylococci, and α­hemolytic streptococci can be cul­

tured when the urine is contaminated during collection

. The percentage distribution of causative organisms in urine cultures was similar to previous studies; E. coli (86.4%) was the commonest pathogen, followed by Klebsiella (4.2%). In addition, Enterococcus, Enterobacter, Proteus, Citrobacter, and Staphylococcus were major causative

As the number of antibiotic­resistant strains has been rapidly increasing, it is more difficult to treat patients with UTI. Because pediatric patients are more likely to have high morbidity and mortality when infected by resistant bacteria and the use of non­susceptible antibiotic may confer a poor prognosis, it is essential to select appropriate empirical anti­

biotics after considering the antibiotic susceptibility pat­

terns

.

Thus, we investigated the antibiotic susceptibility pat­

terns of E. coli that was the most common cause of UTI.

Antimicrobial susceptibility to ampicillin was steadily low in both periods A and B. E. coli has two strains, 29A and 29B, of which 29A was resistant to ampicillin but showed a Table 3. Comparison of Clinical Presentations according to

Susceptibility to Third-generation Cephalosporins No. of episodes(%)

P value 3rd CEP(+)

(N=443) 3rd CEP(-) (N=66)

Age(months) 7.85±100.15 13.28±103.72 0.081

Fever duration(day) 3.37±6.63 3.58±6.42 0.264 Change of antibiotics

during treatment 42(9.5) 14(21.2) 0.011

Hospitalization within

previous 3 mon 47(10.6) 15(22.7) 0.011

Abbreviations: 3

CEP : third-generation cephalosporin.

Table 4. Comparison of Laboratory Findings and Clinical Characteristics between the ESBL-producing and the non-ESBL-Producing Escherichia coli Infection Groups

No. of episodes(%)

P value

ESBL (N=45) Non-ESBL (N=464)

Age (months) 14.24±102.76 7.85±100.15 0.074

Fever duration (day) 2.69±5.31 2.36±5.64 0.109

WBC (cell/mm

) 14,760.2±10,869.80 13,638.81±22,811.19 0.153

CRP (mg/dL) 6.51±22.46 5.73±21.27 0.37

ESR (mm/hr) 14.71±68.29 18.86±100.14 0.245

Males younger than 1yr 28 (62.3) 334 (72.0) 0.239

Females older than 1 yr 7 (15.6) 43 (9.3) 0.134

Change of antibiotics during treatment 10 (22.2) 45 (9.7) 0.005

Vesicoureteral reflux 7 (15.6) 57 (12.2) 0.437

Hospitalization within previous 3 mon 11 (24.4) 49 (10.6) 0.005

Recurrence of UTI in 6 mon 7 (15.6) 44 (9.5) 0.215

Abbreviations: WBC, white blood cell; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ESBL, extended-Spectrum β –lactamase.

higher level of resistance after receiving ampicillin, and 29B was previously susceptible to ampicillin but showed resistance after ampicillin administration. It is believed that susceptibility to ampicillin, one of the most common antibiotics that can be prescribed from the newborn period, was steadily low due to this mechanism

.

The susceptibility of E. coli to trimethoprim/sulfame­

thoxazole (TMP/SMX) was moderate at 72.1% in period A, and 70.7% in period B, respectively. We concluded that TMP/SMX was not satisfactory as a primary antibiotic for the treatment of UTI. Lee et al. showed that the average resistance of E. coli to TMP/SMX was 34.3%

. It has also been reported that susceptibility to TMP/SMX was 52.38

% (1995–2000), 50.00% (2001–2005) and 48.1% (2003–2005), 50.0% (2006–2008) in two other studies, respectively

. Overall, susceptibility of E. coli to TMP/SMX was low in pediatric UTI patients, despite the variation of the results obtained in several studies. This is supported by the cross­

resistance mechanism, that is, resistance to trimethoprim also shows as resistance to TMP/SMX, ampicillin, ampi­

cillin/clavulanate, and quinolone

.

Majority of study results showed that amikacin had a susceptibility higher than 90%. In this study, amikacin also showed susceptibilities as high as 99.4% and 99.3% in both periods A and B, respectively. Amikacin should be used with careful consideration of complications such as ototo­

xicity and nephrotoxicity in children with UTI, and their serum creatinine levels should be constantly monitored.

Third­generation cephalosporin, which has shown high susceptibility in many studies and has been most commonly used in the treatment of pediatric UTI, also showed signifi­

cantly reduced susceptibility in this study. The suscepti­

bility was as high as 91.7% in period A, but significantly decreased to 75.5% in period B. Other studies also showed similar results. Jang et al.’s five­year study (1993–1997) identified that resistance of E. coli to ceftazidime increased from 3% to 14%

. Lee et al. also determined that the re­

sistance to third­generation cephalosporin increased to 2.1% in 2000–2004, 8.3% in 2005–2009, and 8.8% in 2010–

2014. This may be due to the gradually increasing resistance due to extensive use of third­generation cephalosporins for urinary tract, upper respiratory, and gastrointestinal infections. Even if the diagnosis is uncertain, the tendency to use antibiotics with a wide range of antimicrobial activity

is also considered one of the causes

. Another study reported that the continuous increase in the use of third­

generation cephalosporins has led to increased E. coli resistance (from 14% to 50%)

. The results of our study showed that patients with resistance to third­generation cephalosporins were more likely to have been hospitalized in the preceding 3 months, and were also more likely to have changed antibiotics after initial treatment failure.

These two differences were statistically significant, and it is thought that the same factors would have affected the B group, since they showed a higher detection rate of third­

generation cephalosporin­resistant bacteria in culture tests.

Because we were unable to obtain medication histories for antibiotics prescribed outside our hospital, it was not pos­

sible to ascertain the precise frequency of previous antibiotic use. Thus, we postulated that the rate of antibiotic exposure would be higher among older patients, and investigated antibiotic susceptibility by age of diagnosis. We observed that patients showing third­generation cephalosporin su­

sceptibility were 5 months younger, on average, than pa­

tients showing resistance, although this difference was not statistically significant. Thus, we expect that antibiotic me­

dication history will also have an effect on susceptibility.

Quinolone is commonly used to treat cystitis in adults, but is rarely prescribed in children due to several side ef­

fects. In children, the use of quinolone has been approved only for cystic fibrosis, immunosuppression, severe typhoid fever, paratyphoid, and complicated urinary tract infection.

However, studies using young animals showed that cartil­

age lesions were found in joints as a result of quinolone administration. Moreover, other reported side effects were increased QT interval on electrocardiogram, gastrointe­

stinal damage, central nervous system damage, and photo­

sensitivity, thereby requiring careful administration

. In this study, E. coli’s susceptibility to quinolone was signifi­

cantly reduced from 88.4% to 78.2%. Lee et al. reported that the resistance to quinolone increased to 7.9% in 2000–

2004, 9.7% in 2005–2009, and 12.4% in 2010–2014

. A study found that drug resistance occurred through me­

chanisms that cannot be understood by similar drugs or other irrelevant drugs even without exposure. Another study argued that the conjugation of qnr (a plasmid­me­

diated quinolone gene, derived from other avirulent bac­

teria) into E. coli or K. pneumoniae (virulent bacteria) was

an important mechanism of pediatric quinolone drug re­

sistance development

. Therefore, quinolone abuse should be prevented in adults because it can cause resistance in children.

In recent years, the incidence of ESBL­producing gram­

negative bacteria has increased, making it difficult to choose antibiotics. ESBLs are β­lactamases that hydrolyze cepha­

losporin and monobactams with an oxyimino side chain via a plasmid­mediated mechanism. Therefore, they have multi­resistance to antibiotics related to oxyimino­ β­

lactams

. This resistance is mainly observed in E. coli and Klebsiella as well as other intestinal bacteria. It has been increasingly observed in bacteria, such as K. pneumoniae, Pseudomonas species, and E. coli worldwide. In Korea, ESBL­producing bacteria have been reported since the 1990s and have increased rapidly over the past decade. The incidence of ESBL in Korea was 4.8–7.5% in Pai et al., study from 1994 to 1998, 10.8% in Lee et al.’s study from 2001 to 2003, 11.03% in Park et al., study from 2008 to 2010, and 13.6% in Ahn et al.’s study from 2011 to 2013, indicating a continuous increase

. In this study, a total of 45 ESBL­

producing strains were found, all of which were E. coli. The percentage of ESBL­producing strains was 6.1% in period A and 17.1% in period B, thus showing a statistically signifi­

cant increase in the incidence rate. In a study by Lee et al., the percentage of ESBL­producing strains continuously increased to 1.4%, 7.6%, and 8.2% over the three periods

. Risk factors for increased ESBL­producing Gram­negative bacteria are decreased immunity, long­term hospitaliza­

tion, and frequent use of cephalosporins due to the infec­

tion history, such as UTI. In addition, studies have shown that there were a significant number of infections caused by ESBL+ strains in male infants younger than 1­year­old and female infants older than 1­year­old. A study showed that risk factors included history of anatomical/functional urinary anomalies, recurrent urinary tract infections and sepsis, as well as hospital admission in the last 3 months

. In the results of our study, there were no significant diffe­

rences between the ESBL­producing E. coli infection group and the non­ESBL­producing E. coli infection group regar­

ding age, fever duration, or blood tests. However, the ESBL­

producing group showed significantly higher rates of hos­

pitalization in the preceding 3 months and change of anti biotics during treatment due to persistent fever. Also,

the ESBL­producing E. coli group tended to show higher recurrence rates for vesicoureteral reflux and UTI, although this difference was not statistically significant. The recur­

rence rate and failure rate of UTI treatment due to ESBL­

producing E. coli are high; therefore, the necessity of guide­

lines for antimicrobial therapy has developed. In this study, all of the children infected by ESBL+ strains were suscep­

tible to carbapenem and 82% were susceptible to quinolone.

Other studies also recommended carbapenem and quino­

lone. Therefore, these antibiotics should be used while care­

fully monitoring changes in antibiotic susceptibility.

This study has limitations because of the small sample size (589 for >8 years) with an uneven age distribution and was conducted in a limited local community. In addition, there was a large gap in the number of patients during the two comparative periods. Therefore, further studies should be conducted to overcome these limitations.

In conclusion, ampicillin and TMP/SMX, which are widely used as conventional antibiotics for treating pediatric UTI, may no longer be appropriate. Due to the decreased susceptibility to third­generation cephalosporin and qui­

nolone depending on the period and continuously increa­

sing ESBL strains, the discovery and use of appropriate antibiotics are required.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

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